Substituted pyrazolo [1,5-A] pyrimidinyls and pharmaceutical uses therefore

ABSTRACT

The present invention provides compounds of formula (I): 
                         
pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a 371 Application of PCT/US03/13395, filed 30 Apr.2003, which claims priority to U.S. application Ser. No. 60/379,421,filed 10 May 2002.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, pharmaceuticalformulations comprising these compounds, and the use of these compoundsin therapy. More particularly, the present invention relates tocompounds for the prophylaxis and treatment of herpes viral infections.

Of the DNA viruses, those of the herpes group are the sources of themost common viral illnesses in man. The group includes herpes simplexvirus types 1 and 2 (HSV), varicelia zoster virus (VZV), cytomegalovirus(CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6),human herpes virus type 7 (HHV-7) and human herpes virus type 8 (HHV-8).HSV-1 and HSV-2 are some of the most common infectious agents of man.Most of these viruses are able to persist in the host's neural cells;once infected, individuals are at risk of recurrent clinicalmanifestations of infection which can be both physically andpsychologically distressing.

Herpes simplex viruses (HSV-1 and -2) are the causative agents of herpeslabialis and genital herpes. HSV infection is often characterised byextensive and debilitating lesions of the skin, mouth and/or genitals.Primary infections may be subclinical although tend to be more severethan infections in individuals previously exposed to the virus. Ocularinfection by HSV can lead to keratitis or cataracts thereby endangeringthe host's sight. Infection in the new-born, in immunocompromisedpatients or penetration of the infection into the central nervous systemcan prove fatal. In the US alone, 40 million individuals are infectedwith HSV-2, a number that is expected to increase to 60 million by 2007.Over 80% of individuals infected with HSV-2 are unaware they carry andspread the virus, and of those diagnosed less than 20% received oraltherapies. The net result is that less than 5% of the infectedpopulation are treated. Likewise of the 530 million individualsworldwide who carry the HSV-1 virus, 81% of the symptomatic populationremain untreated. No cure exists for HSV infection, and once infected,individuals carry the virus for life in a dormant state. Reactivation ofthe virus from latency occurs periodically and may be triggered bystress, environmental factors, and/or suppression of the host immunesystem. Currently, the use of nucleoside analogs such as valaciclovir(VALTREX®) and aciclovir (ZOVIRAX®) is the standard of care for managinggenital herpes virus outbreaks.

Varicella zoster virus (VZV) (also known as herpes zoster virus) is aherpes virus which causes chickenpox and shingles. Chickenpox is theprimary disease produced in a host without immunity, and in youngchildren is usually a mild illness characterised by a vesicular rash andfever. Shingles or zoster is the recurrent form of the disease whichoccurs in adults who were previously infected with VZV. The clinicalmanifestations of shingles are characterised by neuralgia and avesicular skin rash that is unilateral and dermatomal in distribution.Spread of inflammation may lead to paralysis or convulsions. Coma canoccur if the meninges become affected. VZV is of serious concern inpatients receiving immunosuppressive drugs for transplant purposes orfor treatment of malignant neoplasia and is a serious complication ofAIDS patients due to their impaired immune system.

In common with other herpes viruses, infection with CMV leads to alifelong association of virus and host. Congenital infection followinginfection of the mother during pregnancy may give rise to clinicaleffects such as death or gross disease (microcephaly,hepatosplenomegaly, jaundice, mental retardation), retinitis leading toblindness or, in less severe forms, failure to thrive, andsusceptibility to chest and ear infections. CMV infection in patientswho are immunocompromised for example as a result of malignancy,treatment with immunosuppressive drugs following transplantation orinfection with Human Immunodeficiency Virus, may give rise to retinitis,pneumonitis, gastrointestinal disorders and neurological diseases. CMVinfection is also associated with cardiovascular diseases and conditionsincluding restenosis and atherosclerosis.

The main disease caused by EBV is acute or chronic infectiousmononucleosis (glandular fever). Examples of other EBV or EBV associateddiseases include lymphoproliferative disease which frequently occurs inpersons with congenital or acquired cellular immune deficiency, X-linkedlymphoproliferative disease which occurs namely in young boys,EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngealcarcinoma, Burkitt lymphoma, non-Hodgkin lymphoma, thymomas and oralhairy leukoplakia. EBV infections have also been found in associationwith a variety of epithelial-cell-derived tumours of the upper and lowerrespiratory tracts including the lung. EBV infection has also beenassociated with other diseases and conditions including chronic fatiguesyndrome, multiple sclerosis and Alzheimer's disease.

HHV-6 has been shown to be a causative agent of infantum subitum inchildren and of kidney rejection and interstitial pneumonia in kidneyand bone marrow transplant patients, respectively, and may be associatedwith other diseases such as multiple sclerosis. There is also evidenceof repression of stem cell counts in bone marrow transplant patients.HHV-7 is of undetermined disease aetiology.

Hepatitis B virus (HBV) is a viral pathogen of world-wide majorimportance. The virus is aetiologically associated with primaryhepatocellular carcinoma and is thought to cause 80% of the world'sliver cancer. Clinical effects of infection with HBV range fromheadache, fever, malaise, nausea, vomiting, anorexia and abdominalpains. Replication of the virus is usually controlled by the immuneresponse, with a course of recovery lasting weeks or months in humans,but infection may be more severe leading to persistent chronic liverdisease outlined above.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided acompound of formula (I):

wherein:

p is 1, 2 or 3;

-   each R¹ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay,    —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰NHSO₂R⁹, —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹,    —R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹,    —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,    —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano,    nitro and azido;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹,        —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;    -   n is 0, 1 or, 2;

Y is N or CH;

-   R² is selected from the group consisting of Ay, Het, —OAy, —OHet,    —OR¹⁰Ay, —OR¹⁰Het, —NR ⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy,    —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹, —R¹⁰OR⁷,    —R¹⁰cycloalkyl, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   Ring A is selected from the group consisting of aryl, 5-10 membered    heterocyclic group and a 5-10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5; and-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)N R⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet,    —NHR¹⁰Ay, —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,    —R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,    —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰ C(NH)NR⁹R¹¹,    —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,    —R¹⁰SO₂NHCOR⁹, cyano, nitro and azido;    or a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

In another aspect of the invention there is provided a pharmaceuticalcomposition comprising a compound of formula (I). In one embodiment, thepharmaceutical composition further comprises a pharmaceuticallyacceptable carrier or diluent. In one embodiment, the pharmaceuticalcomposition further comprises an antiviral agent selected from the groupconsisting of aciclovir and valaciclovir.

In a third aspect of the invention, there is provided a method for theprophylaxis or treatment of a herpes viral infection in an animal. Themethod comprises administering to the animal a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof. Theherpes viral infection can be any of herpes simplex virus 1, herpessimplex virus 2, cytomegalovirus, Epstein Barr virus, varicella zostervirus, human herpes virus 6, human herpes virus 7, and human herpesvirus 8.

In a fourth aspect, there is provided a method for the prophylaxis ortreatment of a condition or disease associated with a herpes viralinfection in an animal. The method comprises administering to the animala therapeutically effective amount of the compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof.

In another aspect, there is provided a process for preparing a compoundof formula (I) comprising reacting the compound of formula (VII-A):

-   -   wherein X is chloro, bromo or iodo;        with a compound of formula (VIII):

-   -   wherein M is selected from the group consisting of —B(OH)₂,        —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, Mg-halide where Ra        is alkyl or cycloalkyl and halide is halo.

In another aspect, the present invention provides a radiolabeledcompound of formula (I) or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof. In one embodiment, thepresent invention provides a tritiated compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. In another aspect, the present invention provides abiotinylated compound of formula (I) or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof.

In another aspect, the present invention provides a compound of formula(I) for use in therapy.

In yet another aspect, the present invention provides a compound offormula (I) for use in the prophylaxis or treatment of a herpes viralinfection.

In yet another aspect, the present invention provides a compound offormula (I) for use in the prophylaxis or treatment of a condition ordisease associated with a herpes viral infection in an animal.

In yet another aspect, the present invention provides the use of acompound of formula (I) for the preparation of a medicament for theprophylaxis or treatment of a herpes viral infection in animal,particularly humans.

In yet another aspect, the present invention provides the use of acompound of formula (I) for the preparation of a medicament for thetreatment or prophylaxis of diseases or conditions associated with aherpes viral infection in animals, preferrably humans.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “a compound of the invention” or “a compound of formula(I)” means a compound of formula (I) or a pharmaceutically acceptablesalt, solvate, or physiologically functional derivative thereof.Similarly, with respect to isolatable intermediates such as for example,compounds of formula (VII), (VI), (V) and (IV), the phrase “a compoundof formula (number)” means a compound having that formula andpharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives thereof.

As used herein, the terms “alkyl” (and “alkylene”) refer to straight orbranched hydrocarbon chains containing from 1 to 8 carbon atoms.Examples of “alkyl” as used herein include, but are not limited to,methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, andtert-butyl. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, propylene, butylene, and isobutylene.“Alkyl” also includes substituted alkyl. The alkyl groups may beoptionally substituted with one or more substituents selected from thegroup consisting of mercapto, nitro, cyano and halo. Perhaloalkyl, suchas trifluoromethyl is one particular alkyl group.

As used herein, the term “cycloalkyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms and no carbon-carbondouble bonds. “Cycloalkyl” includes by way of example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.“Cycloalkyl” also includes substituted cycloalkyl. The cycloalkyl may beoptionally substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo and alkyl.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing from 2 to 8 carbon atoms and at least oneand up to three carbon-carbon double bonds. Examples of “alkenyl” asused herein include, but are not limited to ethenyl and propenyl.“Alkenyl” also includes substituted alkenyl. The alkenyl groups mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo and alkyl.

As used herein, the term “cycloalkenyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms (unless otherwisespecified) and up to 3 carbon-carbon double bonds. “Cycloalkenyl”includes by way of example cyclobutenyl, cyclopentenyl and cyclohexenyl.“Cycloalkenyl” also includes substituted cycloalkenyl. The cycloalkenylmay optionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo and alkyl.

As used herein, the term “alkynyl” refers to straight or branchedhydrocarbon chains containing from 2 to 8 carbon atoms and at least oneand up to three carbon-carbon triple bonds. Examples of “alkynyl” asused herein include, but are not limited to ethynyl and propynyl.“Alkynyl” also includes substituted alkynyl. The alkynyl groups mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo and alkyl.

The term “halo” or “halogen” refers to the elements fluorine, chlorine,bromine and iodine.

The term “aryl” refers to monocyclic carbocyclic groups and fusedbicyclic carbocyclic groups having from 5 to 12 carbon atoms and havingat least one aromatic ring. Examples of particular aryl groups includebut are not limited to phenyl, and naphthyl. “Aryl” also includessubstituted aryl. Aryl groups may optionally be substituted on anavailable carbon with one or more substituents selected from the groupconsisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl,cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy,alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide,sulfonamide, Het, amidine, cyano, nitro and azido. Particular arylgroups according to the invention include but are not limited to phenyland substituted phenyl.

The term “heterocyclic” (or “heterocycle”) refers to a monocyclicsaturated or unsaturated non-aromatic groups and fused bicyclicnon-aromatic groups, having the specified number of members andcontaining 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examplesof particular heterocyclic groups include but are not limited totetrahydrofuran, dihydropyran, tetrahydropyran, pyran, oxetane,thietane, 1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine,piperazine, tetrahydropyrimidine, pyrrolidine, morpholine,thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran,tetrahydrothiophene, and the like. “Heterocyclic” also includessubstituted heterocyclic. The heterocyclic groups may optionally besubstituted on an available carbon or heteroatom with one or moresubstituents selected from the group consisting of halo, alkyl(including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Particular heterocyclic groups according to theinvention include but are not limited to pyrrolidine, piperidine,morpholine, thiomorpholine and piperazine and substituted variantsthereof.

The term “heteroaryl” refers to aromatic monocyclic groups and aromaticfused bicyclic groups (having at least one aromatic ring) having thespecified number of members and containing 1, 2, 3, or 4 heteroatomsselected from N, O and S. Examples of particular heteroaryl groupsinclude but are not limited to furan, thiophene, pyrrole, imidazole,pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,quinoline, isoquinoline, benzofuran, benzothiophene, indole, andindazole. “Heteroaryl” also includes substituted heteroaryl. Theheteroaryl groups may optionally be substituted on an available carbonor heteroatom with one or more substituents selected from the groupconsisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl,cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy,alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide,sulfonamide, Het, amidine, cyano, nitro and azido. Particular heteroarylgroups according to the invention include but are not limited topyridine, furan, thiophene, pyrrole, imidazole, pyrazole and pyrimidine,and substituted variants thereof.

The term “members” (and variants thereof e.g., “membered”) in thecontext of heterocyclic and heteroaryl groups refers to the total atoms,carbon and heteroatoms N, O and/or S, which form the ring. Thus, anexample of a 6-membered heterocyclic ring is piperidine and an exampleof a 6-membered heteroaryl ring is pyridine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and events that do not occur.

The present invention provides compounds of formula (I):

wherein:p is 1, 2 or 3;

-   each R¹ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay,    —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰NHSO₂R⁹, —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹,    —R¹⁰OC(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰C(O)NR⁹R¹¹, R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro    and azido;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹,        —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;    -   n is 0, 1 or 2;-   Y is N or CH;-   R² is selected from the group consisting of Ay, Het, —OAy, —OHet,    —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy,    —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹, —R¹⁰OR⁷,    —R¹⁰cycloalkyl, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   Ring A is selected from the group consisting of aryl, 5-10 membered    heterocyclic group and a 5-10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5; and-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay,    —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰R⁹,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹,    cyano, nitro and azido;    and pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

In one embodiment, p is 1 or 2. In one particular embodiment, p is 1.

R¹ may be at the C-5, C-6 and/or C-7 positions.

Compounds of formula (I) include those compounds defined wherein atleast one R¹ contains an aryl, heterocyclic or heteroaryl moiety. Ay,Het, —C(O)Ay, —C(O)Het, —C(O)NR⁷Ay, —C(NH)NR⁷Ay, —OAy, —OHet, —OR¹⁰Ay,—OR¹⁰Het, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —S(O)_(n)Ay,—S(O)_(n)Het, —S(O)₂NR⁷Ay, —R¹⁰Ay, —R¹⁰NR⁷Ay, —R¹⁰C(O)Ay, —R¹⁰C(O)Het,—R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁷Ay and —R¹⁰C(O)NHR¹⁰Het, areexamples of groups containing an aryl, heterocyclic or heteroarylmoiety. In one embodiment, the compounds of the present inventioninclude those compounds defined wherein at least one R¹ contains aheterocyclic or heteroaryl moiety such as Het, —C(O)Het, —OHet,—OR¹⁰Het, —NHHet, —NHR¹⁰Het, —S(O)_(n)Het, —R¹⁰C(O)Het, —R¹⁰OC(O)Het and—R¹⁰C(O)NHR¹⁰Het. Another class of compounds of formula (I) includesthose compounds defined wherein R¹ does not contain an aryl,heterocyclic or heteroaryl moiety. In this embodiment R¹ is typicallyhalo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —C(O)R⁹,—CO₂R⁹, —C(O)NR⁷R⁸, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —OR⁷, —NR⁷R⁸, —S(O)_(n)R⁹,—S(O)₂NR⁷R⁸, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NHSO₂R⁹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹,—R¹⁰OS(O)_(n)R⁹, cyano, nitro and azido. In another class of compoundsof formula (1), R¹ does not contain a heterocyclic or heteroaryl moietybut may contain an aryl moiety. In this embodiment, R¹ is typicallyselected from the group consisting of halo, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, Ay, —C(O)R⁹, —C(O)Ay, —CO₂R⁹, —C(O)NR⁷R⁸,—C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷, —OAy, —OR¹⁰Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHSO₂R⁹, —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,—R¹⁰OC(O)Ay, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹,—R¹⁰OS(O)_(n)R⁹, cyano, nitro and azido.

In one embodiment, R¹ is at the C-7 position.

In one embodiment, each R¹ is the same or different and is independentlyselected from the group consisting of halo, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, —S(O)₂NR⁷R⁸ —S(O)₂NR⁷Ay, cyano, nitro and azido, or anysubset thereof. More particularly, each R¹ is the same or different andis independently selected from the group consisting of halo, Ay, Het,—NR⁷R⁸, —NHHet, —S(O)_(n)R⁹, —S(O)_(n)Ay, and cyano, or any subsetthereof. In one embodiment, each R¹ is the same or different and isindependently selected from the group consisting of halo, Ay, Het and—NR⁷R⁸, or any subset thereof.

More specifically, in one embodiment, each R¹ may be the same ordifferent and is independently selected from the group consisting of Cl,Ay, —NH₂, —NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl), Het,—Nalkyl-O-alkyl, and NHAy, or any subset thereof. Specific examples ofsome particular R¹ groups are selected from the group consisting of Cl,phenyl, —NH₂, —NH-methyl, —N(CH₃)₂, —NH-cyclopentyl, —NH-cyclopropyl,—NH-isopropyl, —NH-phenyl, —N(CH₂)₂OCH₃, and pyrrolidine, or any subsetthereof.

In one class of compounds of formula (I), Y is CH. In another class ofcompounds of formula (I), Y is N.

In another embodiment, the compounds of formula (I) include thosecompounds defined where at least one R² contains an aryl, heterocyclicor heteroaryl moiety. A further embodiment includes those compounds offormula (I) where no R² contains a heterocyclic or heteroaryl moiety. Inanother embodiment, no R² contains an aryl, heterocyclic or heteroarylmoiety. From the embodiments described above with respect to R¹, oneskilled in the art can readily determine the groups defining R² whichcontain or exclude aryl, heterocyclic and/or heteroaryl moieties.

In one embodiment, R² is selected from the group consisting of Het,—NR⁷R⁸, —NR⁷Ay, —NHHet and —S(O)_(n)R⁹, or any subset thereof. Moreparticularly, R² is selected from the group consisting of Het, —NR⁷R⁸,—NR⁷Ay and —S(O)_(n)R⁹, or any subset thereof. In one embodiment, R² isselected from the group consisting of Het and —NR⁷R⁸. In anotherembodiment, R² is —NR⁷R⁸. In another particular embodiment, R² is—NR⁷-cycloalkyl.

In a particular embodiment, R² is selected from the group consisting of—NH₂, —NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl), Het (e.g.,pyrrolidine), —NHHet and —NH-alkyl-Het, or any subset thereof. Moreparticularly, R² is selected from the group consisting of —NH-alkyl and—NH-cycloalkyl, or any subset thereof.

Specific examples of some particular R² groups are selected from thegroup consisting of —NH₂, —NH-methyl, —NH-ethyl, —NH-propyl,—NH-isopropyl, —NH-cyclopropyl, —NH-butyl, —NH-isobutyl, —NH-cyclobutyl,—NH-cyclopentyl, —NH-cyclohexyl, —NH(CH₂)₂OCH₃, and pyrrolidine (e.g.,pyrrolidine bonded through N). In one embodiment, R² is —NH-cyclopentyl.

In one embodiment, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, R¹⁰-cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —C(O)R⁹, and R¹⁰CO₂R⁹,or any subset thereof. More particularly, R⁷ and R⁸ are each the same ordifferent and are independently selected from the group consisting of H,alkyl, cycloalkyl and R¹⁰-cycloalkyl, or any subset thereof. In oneembodiment, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl andcycloalkyl or any subset thereof.

The group —R¹⁰(OR¹⁰)_(w) in the definition of R⁹ and R¹¹ refers to alinear PEG-like chain. In one embodiment, R⁹ and R¹¹ are each the sameor different and are independently selected from the group consisting ofH, alkyl, cycloalkyl, and —RB¹⁰-cycloalkyl, or any subset thereof. Moreparticularly, R⁹ and R¹¹ are each the same or different and are eachindependently selected from the group consisting of H and alkyl, or anysubset thereof.

In one embodiment, R¹⁰ is alkyl or cycloalkyl; more particularly alkyl.

In another embodiment, the compounds of formula (I) include thosecompounds defined where at least one of R³ and R⁴ contains aheterocyclic or heteroaryl moiety. A further embodiment includes thosecompounds of formula (I) where neither R³ nor R⁴ contain a heterocyclicor heteroaryl moiety. From the embodiments described above with respectto R¹, one skilled in the art can readily determine the groups definingR³ and R⁴ which contain or exclude aryl, heterocyclic and/or heteroarylmoieties.

In one embodiment, R³ is selected from the group consisting of H, halo,alkyl, Ay, —OR⁷, —CO₂R⁷, —NR⁷R⁸, —R¹⁰OR⁷ and —R¹⁰NR⁷R⁸, or any subsetthereof. More particularly, R³ is selected from the group consisting ofH, halo, alkyl, —OR⁷ and —NR⁷R⁸, or any subset thereof. In oneparticular embodiment R³ is H or alkyl. In one embodiment R³ is H.

In one embodiment, R⁴ is selected from the group consisting of H, halo,alkyl, Ay, —OR⁷, —CO₂R⁷, —NR⁷R⁸, —R¹⁰R⁷ and —R¹⁰NR⁷R⁸, or any subsetthereof. More particularly R⁴ is selected from the group consisting ofH, halo, alkyl, OR⁷ and —NR⁷R⁸, or any subset thereof. In one particularembodiment, R⁴ is H or alkyl. In one embodiment R⁴ is H.

in formula (I) above is herein referred to as “Ring A.”

Ring A is aryl, a 5-10 membered heterocyclic group (including a 1, 2, 3or 4 heteroatoms selected from N, O and S) or a 5-10 membered heteroarylgroup (including 1, 2, 3 or 4 heteroatoms selected from N, O and S).Ring A may be bonded to the C-2 carbon of the fused ring through anysuitable atom including any suitable heteroatom. In one particularembodiment, Ring A is selected from the group consisting of aryl, a 5-10membered heterocyclic group containing 1, 2 or 3 heteroatoms selectedfrom N, O and S and a 5-10 membered heteroaryl group containing 1, 2 or3 heteroatom's selected from N, O and S.

In one embodiment, Ring A is selected from the group consisting of aryl,a 5-6 membered heterocyclic or heteroaryl group and a 9-memberedheterocyclic or heteroaryl group. In one particular embodiment, Ring Ais selected from the group consisting of aryl; a 5-6 memberedheterocyclic or heteroaryl group containing 1, 2 or 3 heteroatomsselected from N, O and S; and a 9-membered heterocyclic or heteroarylgroup containing 1, 2 or 3 heteroatoms selected from N, O and S.

In one embodiment, Ring A is selected from the group consisting ofphenyl, naphthyl, furan, pyridine, pyrimidine, thiazole, pyrazine,pyrrole, imidazole, oxazole, benzimidazole, quinoline, isoquinoline, andquinoxoline, or any subset thereof. More particularly, Ring A in formula(I) is selected from the group consisting of phenyl, furan, pyridine andpyrimidine. In one embodiment, Ring A contains at least one N atom andis bonded through N. In another embodiment, Ring A is phenyl.

In one embodiment q is 0, 1 or 2. In one particular embodiment, q is 0.In another particular embodiment, q is 1. In one embodiment, q is 2.

R⁵ may be in the ortho, meta and/or para position.

One class of compounds of formula (I) includes those compounds definedwherein at least one R⁵ group contains an aryl, heterocyclic orheteroaryl moiety (in one embodiment, a heterocyclic or heteroarylmoiety). Another class of compounds of formula (I) includes thosecompounds defined wherein no R⁵ group contains an aryl, heterocyclic orheteroaryl moiety (or in one embodiment no R⁵ group contains aheterocyclic or heteroaryl moeity).

In one embodiment, each R⁵ group is the same or different and isindependently selected from the group consisting of halo, alkyl,alkenyl, Ay, Het, —CO₂R⁹, —C(O)NR⁷R⁸, —R⁷, —OAy, —NR⁷R⁸, —NR⁷Ay,—S(O)₂NR⁷R⁸, cyano, nitro and azido, or any subset thereof. Moreparticularly, each R⁵ group is the same or different and isindependently selected from the group consisting of halo, alkyl,alkenyl, Ay, Het, —OR⁷, —NR⁷R⁸, —NR⁷Ay, cyano, nitro and azido, or anysubset thereof. In one particular embodiment, each R⁵ group is the sameor different and is independently selected from the group consisting ofhalo, alkyl, —OR⁷, —NR⁷R⁸ and cyano, or any subset thereof.

More specifically, in one embodiment, the compounds of formula (I) aredefined where each R⁵ is the same or different and is independentlyselected from the group consisting of H, halo (e.g., fluoro, chloro orbromo), alkyl (e.g., methyl), O-alkyl (e.g., O-methyl, O-isobutyl, and

cyano, —NH—CH₃, and —N(CH₃)₂, or any subset thereof.

It is to be understood that the present invention includes allcombinations and subsets of the particular groups defined hereinabove.

Specific compounds of formula (I) include but are not limited to:

-   3-(2-Fluoropyridin-4-yl)-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine;-   N-Cyclopentyl-4-(2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidin-3-yl)pyridin-2-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)pyridin-4-yl]-2-phenylpyrazolo[1,5-α]pyrimidin-7-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyrimidin-7-amine;    and-   N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine,    and-   and pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

It will be appreciated by those skilled in the art that the compounds ofthe present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate or physiologicallyfunctional derivative thereof. The pharmaceutically acceptable salts ofthe compounds of formula (I) include conventional salts formed frompharmaceutically acceptable inorganic or organic acids or bases as wellas quaternary ammonium salts. More specific examples of suitable acidsalts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric,perchloric, fumaric, acetic, propionic, succinic, glycolic, formic,lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic,methanesulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonichydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Inone embodiment, the compounds of formula (I) are in the form of themesylate salt. Other acids such as oxalic, while not in themselvespharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining the compounds of the invention andtheir pharmaceutically acceptable salts. More specific examples ofsuitable basic salts include sodium, lithium, potassium, magnesium,aluminium, calcium, zinc, N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, N-methylglucamine and procainesalts.

The term “solvate” as used herein refers to a complex of variablestoichiometry formed by a solute (a compound of formula (I)) and asolvent. Solvents, by way of example, include water, methanol, ethanol,or acetic acid.

The term “physiologically functional derivative” as used herein refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide of a compound offormula (I), which upon administration to an animal, particularly amammal, such as a human, is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. See, for example, Burger's Medicinal Chemistry And DrugDiscovery, 5th Edition, Vol 1: Principles And Practice.

Processes for preparing pharmaceutically acceptable salts, solvates andphysiologically functional derivatives of the compounds of formula (I)are conventional in the art. See, e.g., Burger's Medicinal Chemistry AndDrug Discovery 5th Edition, Vol 1: Principles And Practice.

As will be apparent to those skilled in the art, in the processesdescribed below for the preparation of compounds of formula (I), certainintermediates, may be in the form of pharmaceutically acceptable salts,solvates or physiologically functional derivatives of the compound.Those terms as applied to any intermediate employed in the process ofpreparing compounds of formula (I) have the same meanings as noted abovewith respect to compounds of formula (I). Processes for preparingpharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives of such intermediates are known in the art andare analogous to the process for preparing pharmaceutically acceptablesalts, solvates and physiologically functional derivatives of thecompounds of formula (I).

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one, or more chiral centres are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

The present invention further provides compounds of formula (I) for usein medical therapy, e.g. in the treatment or prophylaxis, includingsuppression of recurrence of symptoms, of a viral disease in an animal,e.g. a mammal such as a human. The compounds of formula (I) areespecially useful for the treatment or prophylaxis of viral diseasessuch as herpes viral infections. Herpes viral infections include, forexample, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2),cytomegalovirus (CMV), Epstein Barr virus (EBV), varicella zoster virus(VZV), human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), andhuman herpes virus 8 (HHV-8). Thus, the compounds of the invention arealso useful in the treatment or prophylaxis of the symptoms or effectsof herpes virus infections.

The compounds of the invention are useful in the treatment orprophylaxis of conditions or diseases associated with herpes virusinfections, particularly conditions or diseases associated with latentherpes virus infections in an animal, e.g., a mammal such as a human. Byconditions or diseases associated with herpes viral infections is meanta condition or disease, excluding the viral infection per se, whichresults from the presence of the viral infection, such as chronicfatigue syndrome which is associated with EBV infection; and multiplesclerosis which has been associated with herpes viral infections such asEBV and HHV-6. Further examples of such conditions or diseases aredescribed in the background section above.

In addition to those conditions and diseases, the compounds of thepresent invention may also be used for the treatment or prophylaxis ofcardiovascular diseases and conditions associated with herpes virusinfections, in particular atherosclerosis, coronary artery disease andrestenosis and specifically restenosis following angioplasty (RFA).Restenosis is the narrowing of the blood vessels which can occur afterinjury to the vessel wall, for example injury caused by balloonangioplasty or other surgical and/or diagnostic techniques, and ischaracterized by excessive proliferation of smooth muscle cells in thewalls of the blood vessel treated. It is thought that in many patientssuffering from RFA, viral infection, particularly by CMV and/or HHV-6 ofthe patient plays a pivotal role in the proliferation of the smoothmuscle cells in the coronary vessel treated. Restenosis can occurfollowing a number of surgical and/or diagnostic techniques, forexample, transplant surgery, vein grafting, coronary by-pass graftingand, most commonly following angioplasty.

There is evidence from work done both in vitro and in vivo, indicatingthat restenosis is a multifactorial process. Several cytokines andgrowth factors, acting in concert, stimulate the migration andproliferation of vascular smooth muscle cells (SMC) and production ofextracellular matrix material, which accumulate to occlude the bloodvessel. In addition growth suppressors act to inhibit the proliferationof SMC's and production of extracellular matrix material.

In addition, compounds of formula (I) may be useful in the treatment orprophylaxis of conditions or diseases associated with hepatitis B orhepatitis C viruses, human papilloma virus (HPV) and HIV.

The present invention provides a method for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection, which method comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I).

As used herein, the term prophylaxis refers to the prevention ofinfection, the prevention of occurrence of symptoms in an infectedsubject, the prevention of recurrence of symptoms in an infectedsubject, or a decrease in severity or frequency of symptoms of viralinfection, condition or disease in the subject

As used herein, the term “treatment” refers to the partial or totalelimination of symptoms or decrease in severity of symptoms of viralinfection, condition or disease in the subject, or the elimination ordecrease of viral presence in the subject

As used herein, the term “therapeutically effective amount” means anamount of a compound of formula (I) which is sufficient, in the subjectto which it is administered, to treat or prevent the stated disease,condition or infection. For example, a therapeutically effective amountof a compound of formula (I) for the treatment of a herpes virusinfection is an amount sufficient to treat the herpes virus infection inthe subject.

The present invention also provides a method for the treatment orprophylaxis of a condition or disease associated with herpes viralinfections in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I). In one embodiment, the present inventionprovides a method for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis in an animal such as a mammal (e.g., ahuman), which comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I). The foregoing method isparticularly useful for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis associated with latent infection with aherpes virus.

In another embodiment, the present invention provides a method for thetreatment or prophylaxis of a cardiovascular condition such asatherosclerosis, coronary artery disease or restenosis (particularlyrestenosis following surgery such as angioplasty), which comprisesadministering to the animal a therapeutically effective antiviral amountof the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of hepatitis B or hepatitis C viruses in an animal such as amammal (e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of human papilloma virus in an animal such as a mammal(e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of HIV in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I).

The present invention also provides the use of the compound of formula(I) in the preparation of a medicament for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection; the use of the compound offormula (I) in the preparation of a medicament for the treatment of acondition or disease associated with a herpes viral infection; and theuse of the compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of hepatitis B or hepatitis C viruses,human papilloma virus and HIV. In particular, the present invention alsoprovides the use of a compound of formula (I) in the preparation of amedicament for the treatment or prophylaxis of chronic fatigue syndromeor multiple sclerosis. In one embodiment, the present invention providesthe use of a compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of cardiovascular disease, such asrestenosis and atherosclerosis.

The compounds of formula (I) are conveniently administered in the formof pharmaceutical compositions. Such compositions may conveniently bepresented for use in conventional manner in admixture with one or morephysiologically acceptable carriers or diluents.

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is common topresent the active ingredient as a pharmaceutical formulation orcomposition. The pharmaceutical composition may comprise apharmaceutically acceptable carrier or diluent The carrier(s) ordiluent(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

Accordingly, the present invention further provides for a pharmaceuticalformulation or composition comprising a compound of formula (I). In oneembodiment, the pharmaceutical composition further comprises one or morepharmaceutically acceptable carriers or diluents and optionally, othertherapeutic and/or prophylactic ingredients.

The formulations include those suitable for oral, parenteral (includingsubcutaneous e.g. by injection or by depot tablet, intradermal,intrathecal, intramuscular e.g. by depot and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition, age, and disorder of the recipient as well as the viralinfection or disease being treated. The formulations may conveniently bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. All methods include the step ofbringing into association the compound(s) (“active ingredient”) with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules (including soft-gel capsules), cachetsor tablets (e.g. chewable tablets in particular for paediatricadministration) each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed withother conventional excipients such as binding agents, (for example,syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone), fillers (for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol), lubricants (for example, magnesium stearate, stearic acid,talc, polyethylene glycol or silica), disintegrants (for example, potatostarch or sodium starch glycollate) or wetting agents, such as sodiumlauryl sulfate. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent The tablets may optionally be coated or scored and may beformulated so as to provide slow or controlled release of the activeingredient therein. The tablets may be coated according to methodswell-known in the art

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides. Liquid preparations may also beformulated as soft-gel capsules for oral administration, e.g.,containing conventional soft-gel excipients such as polyethylene glycol.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described. Formulations for rectal administration may bepresented as a suppository with the usual carriers such as cocoa butter,hard fat or polyethylene glycol.

Formulations suitable for topical (e.g., dermal) or intranasalapplication include ointments, creams, lotions, pastes, gels, sprays,aerosols and oils. Suitable carriers for such formulations includepetroleum jelly, lanolin, polyethyleneglycols, alcohols, andcombinations thereof.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured base such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a base such as gelatinand glycerin or sucrose and acacia.

The compounds may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

It will be appreciated that the amount of a compound of the inventionrequired for use in treatment will vary with the nature of the conditionbeing treated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.In general, however, doses employed for adult human treatment willtypically be in the range of 0.02-5000 mg per day, particularly 100-1500mg per day. The desired dose may conveniently be presented in a singledose or as divided doses administered at appropriate intervals, forexample as two, three, four or more sub-doses per day. The formulationsaccording to the invention may contain between 0.1-99% of the activeingredient, conveniently from 30-95% for tablets and capsules and 3-50%for liquid preparations.

The compound of formula (I) for use in the instant invention may be usedin combination with other therapeutic agents for example, non-nucleotidereverse transcriptase inhibitors, nucleoside reverse transcriptaseinhibitors, protease inhibitors and/or other antiviral agents. Theinvention thus provides in a further aspect the use of a combinationcomprising a compound of formula (I) with a further therapeutic agent inthe treatment of viral infections. Particular antiviral agents which maybe combined with the compounds of the present invention includeaciclovir, valaciclovir, fameyclovir, gancyclovir, docosanol, miribavir,amprenavir, lamivudine, zidovudine, and abacavir and pharmaceuticallyacceptable salts or solvates thereof. Particular antiviral agents forcombining with the compounds of the present invention include aciclovirand valaciclovir and pharmaceutically acceptable salts or solvatesthereof. Thus the present invention provides in a further aspect, acombination comprising a compound of formula (I) and an antiviral agentselected from the group consisting of aciclovir and valaciclovir andpharmaceutically acceptable salts or solvates thereof; the use of suchcombination in the treatment of viral infections and the preparation ofa medicament for the treatment of viral infections, and a method oftreating viral infections comprising administering a compound of formula(I) and an antiviral agent selected from the group consisting ofaciclovir and valaciclovir and pharmaceutically acceptable salts orsolvates thereof.

When the compounds of formula (I) are used in combination with othertherapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above optionallytogether with a pharmaceutically acceptable carrier or diluent comprisea further aspect of the invention. The individual components of suchcombinations may be administered either sequentially or simultaneouslyin separate or combined pharmaceutical formulations.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation and may be formulated foradministration. When formulated separately they may be provided in anyconvenient formulation, in such a manner as are known for such compoundsin the art.

When a compound of formula (I) is used in combination with a secondtherapeutic agent active against the viral infection, the dose of eachcompound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

Compounds of formula (I) wherein p is 1 and R¹ is selected from thegroup consisting of Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het and azido, may be conveniently prepared by the processoutlined in Scheme 1 below.

wherein:p is 1;

-   R^(1′) is selected from the group consisting of Het, —OR⁷, —OAy,    —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay,    —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het and azido;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹,        —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;    -   n is 0, 1 or 2;-   Y is N or CH;-   R² is selected from the group consisting of Ay, Het, —OAy, —OHet,    —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy,    —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹, —R¹⁰OR⁷,    —R¹⁰cycloalkyl, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   Ring A is selected from the group consisting of aryl, 5-10 membered    heterocyclic group and a 5-10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay,    —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰OR⁹,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹,    cyano, nitro and azido;-   X is Cl, Br or I; and-   M is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn—halide, ZnRa,    Mg—halide where Ra is alkyl or cycloalkyl and halide is halo.

Generally, the process for preparing the compounds of formula (I)wherein p is 1 and R¹ is selected from the group consisting of Het,—OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay,—NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het and azido, (allformulas and all other variables having been defined above in connectionwith Scheme 1) comprises the steps of:

a) reacting an aminopyrazole of formula (II) with a sodium salt ofethylformyl acetate of formula (III) to prepare a compound of formula(IV);

b) treating the compound of formula (IV) with a chlorinating-dehydratingagent to prepare a compound of formula (V);

c) halogenating the compound of formula (V) to prepare a compound offormula (VI);

d) reacting the compound of formula (VI) with a nucleophile selectedfrom the group consisting of Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het and azido, to prepare a compound of formula (VII); ande) reacting the compound of formula (VII) with a compound of formula(VIII) to prepare a compound of formula (I′).

More specifically, a compound of formula (I) wherein p is 1 and R¹ isselected from the group consisting of Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,—OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het and azido (i.e., a compound of formula (I′),can be prepared reacting the compound of formula (VII) with a compoundof formula (VIII):

-   -   where all variables are as defined above in connection with        Scheme 1.

The reaction may be carried out in an inert solvent, in the presence ofa palladium (0) or nickel (0) catalyst. The reaction may optionally beheated to about 50-150° C. Typically the reaction is performed byreacting equimolar amounts of a compound of formula (VII) with aHet-metal compound of formula (VIII), but the reaction may also beperformed in the presence of an excess of the compound of formula(VIII). The palladium or nickel catalyst is typically present in 1-10mol % compared to the compound of formula (VII). Examples of suitablepalladium catalysts include but are not limited to,tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenyl-phosphine)palladium(II),tris(dibenzylideneacetone)dipalladium (0), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When theHet-metal compound of formula (VIII) is an arylboronic acid or ester oran arylborinate the reaction is more conveniently carried out by addinga base in a proportion equivalent to, or greater than, that of thecompound of formula (VII). Het-metal compounds of formula (VIII) may beobtained from commercial sources or prepared either as discreet isolatedcompounds or generated in situ using methods known to one skilled in theart. (Suzuki, A. J. Organomet Chem. 1999, 576, 147; Stille, J. Angew.Chem. Int. Ed. Engl. 1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60,292).

A compound of formula (VII) can be prepared by reacting a compound offormula (VI) with a suitable nucleophile to provide compounds of formula(VII) wherein R^(1′) is selected from the group consisting of Het, —OR⁷,—OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay,—NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het and azido.

A compound of formula (VI) can be treated with a nucleophile neat or thereaction can be carried out in an inert solvent at room temperature oroptionally with heating to provide compound of formula (VII).Appropriate nucleophiles for substituting the group R^(1′) on the ringwill be apparent to those skilled in the art of organic synthesis.

A compound of formula (VI) can be prepared from a compound of formula(V) via a halogenation procedure.

Typically, the halogenation reaction is carried out by treating thecompounds of formula (V) with a halogenating agent in a suitablesolvent. Suitable halogenating agents include but are not limited to,N-bromosuccinimide, trialkylammonium tribromides, bromine,N-chlorosuccinimide, N-iodosuccinimide, iodine monochloride, and thelike. Suitable solvents include, for example, N,N-dimethylformamide,tetrahydrofuran, dioxane, 1-methyl-2-pyrrolidinone, carbontetrachloride, toluene, dichloromethane, diethyl ether, and the like.

A compound of formula (V) can be prepared from a compound of formula(IV).

Conveniently, this type of transformation can be carried out usingphosphorous oxychloride, optionally in the presence of a base. This isperformed by treating a compound of formula (IV) with phosphorousoxychloride with optional heating. Typically an excess of thedehydrating reagent is used and the reaction can be heated up to refluxtemperature of approximately 105° C. By way of example a particular baseis N,N-diethylaniline and the like.

A compound of formula (IV) can be prepared from a compound of formula(II).

Treatment of the aminopyrazole of formula (II) with sodium salt of ethylformylacetate of formula (III) (prepared from ethyl acetate and ethylformate as described in J. Am. Chem. Soc. 1903, 29, 478) in a suitablesolvent with heating gives a compound of formula (IV). An example of asuitable solvent is ethyl alcohol. Compounds of formula (II) are eithercommercially available or can be prepared by methods known to thoseskilled in the art of organic synthesis.

In addition to the foregoing methods of synthesis, the compounds offormula (I) and pharmaceutically acceptable salts, solvates andphysiologically functional derivatives thereof may also be preparedusing procedures analogous to those described in PCT Publication No.WO02/16359, published to GlaxoSmithKline Inc., the disclosure of whichis incorporated herein by reference in its entirety.

The preparation of compounds of formula (I) wherein thepyrazolo[1,5-α]pyrimidines are substituted at the C-7 position is shownin Scheme 1. Compounds of formula (I) wherein thepyrazolo[1,5-α]pyrimidines exhibit a different substitution pattern atC5, C-6 and C-7 can be obtained using procedures analogous to thosedescribed in Scheme 1 above and by adaptation of procedures found in theliterature (e.g., COMPREHENSIVE HETEROCYCLIC CHEMISTRY, Katritzky A. R.and Rees, C. W. (Eds), 1984, volume 5).

For example, condensation of an aminopyrazole with malonimidate gives5,7-diaminosubstituted pyrazolo[1,5-α]pyrimidines (Arch. Pharm. 1985,318:87-88) that can be elaborated into compounds of formula (I) usingconditions similar to those in Scheme 1. Other disubstituted derivativescan be obtained as described in the literature (Farmaco, 1978, 33:14-20)and elaborated into compounds of formula (I) using the proceduresdescribed in Scheme 1 above.

In particular, the palladium or nickel coupling reaction of thepyrazolo[1,5-α]pyrimidine with the compound of formula (VII) can beaccomplished with pyrazolo[1,5-α]pyrimidines having any of varioussubstitutions represented by (R¹)_(p) in formula (I). Hence, the presentinvention also provides a process for preparing compounds of formula (I)which process comprises reacting a compound of formula (VII-A) with acompound of formula (VIII)

-   -   wherein p and R¹ are as defined in connection with compounds of        formula (I) above and and all variables are defined as in Scheme        1.

As will be apparent to those skilled in the art, a compound of formula(I) may be converted to another compound of formula (I) using techniqueswell known in the art. For example, one method of converting a compoundof formula (I) to another compound of formula (I) comprises a) oxidizingthe compound of formula (I-A) to prepare a compound of formula (I-B) andthen b) optionally reacting a compound of formula (I-B) with an oxygenor amine nucleophile selected from the group consisting of Het bondedthrough N, —OR⁷, —OAr, —OHet, —OR¹⁰Het, —NR⁷R⁸, —NHHet, —NHR¹⁰Ay and—NHR¹⁰Het to produce a compound of formula (I) wherein R² is selectedfrom the group consisting of Het bonded through N, —OR⁷, —OAr, —OHet,—OR¹⁰Het, —NR⁷R⁸, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.

wherein R² is selected from the group consisting of Het bonded throughN, —OR⁷, —OAr, —OHet, —OR¹⁰Het, —NR⁷R⁸, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het,n′ is 1 or 2; and all other variables are as above.

More specifically, a compound of formula (I) can be prepared by reactinga compound of formula (I-B) (i.e., a compound of formula (I) wherein R²is —S(O)_(n)R⁹ where n′ is 1 or 2) with an oxygen or amine nucleophileselected from the group consisting of Het bonded through N, —OR⁷, —OAr,—OHet, —OR¹⁰Het, —NR⁷R⁸, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het. The reactionmay be carried out neat or in a suitable solvent and may be heated to50-150° C. Typically the solvent is a lower alcohol such as methanol,ethanol, isopropanol and the like or solvent such asN,N-dimethylformamide or tetrahydrofuran, and the like. Optionally abase may be used to facilitate the reaction. Typically the base can bepotassium carbonate, or an amine base such as triethylamine.

A compound of the formula (I-B) may be conveniently prepared by reactinga compound of formula (I-A) (i.e., a compound of formula (I) wherein R²is —S(O)_(n)R⁹ where n is 0) with an oxidizing agent in an inertsolvent, optionally in the presence of a base. Typically the oxidizingagent is a peracid such as m-chloroperbenzoic acid or the likeoptionally with a base such as sodium bicarbonate. Careful monitoring ofthe stoichiometry between the oxidizing agent and the substrate allowsthe product distribution between sulfoxide (n=1), and sulfone (n=2) tobe controlled. Suitable solvents include but are not limited to,dichloromethane, chloroform and the like.

Another particularly useful method for converting a compound of formula(I) to another compound of formula (I) comprises reacting a compound offormula (I-C) (i.e., a compound of formula (I) wherein R² is fluoro)with an amine nucleophile (including substituted amines, heterocyclesand heteroaryls, particularly those linked through N), and optionallyheating the mixture to 50-150° C. to prepare a compound of formula (I-D)(i.e., a compound of formula (I) wherein R^(2′) is selected from thegroup consisting of Het, —NR⁷R⁸, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het).

wherein R^(2′) is selected from the group consisting of Het, —NR⁷R⁸,—NHHet, —NHR¹⁰Ay, and —NHR¹⁰Het all other variables are as definedabove.

This procedure may be carried out by mixing a compound of formula (I-C)in a neat amine, or in a suitable solvent with an excess of amine toproduce a compound of formula (I-D). Typically the solvent is a loweralcohol such as methanol, ethanol, isopropanol or the like. Othersuitable solvents may include N,N-dimethyl-formamide,1-methyl-2-pyrrolidine and the like.

As a further example, a compound of formula (I-E) (i.e., where X¹ ishalogen) may be converted to a compound of formula (I-F) using aminationtechniques known to those skilled in the art.

wherein:

-   X¹ is halo, such as chloro, bromo or iodo;-   Amine is selected from the group consisting of Het bonded through N,    —NR⁷R⁸, —NHHet, —NHR¹⁰Ar and —NHR¹⁰Het;-   p′ is 0, 1 or 2.-   and all other variables are as defined above.

The reaction can be carried out via an adaptation of procedures found inthe literature (Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000,65,1144) wherein a compound of the formula (I-E) is treated with anamine, a palladium (0) or nickel (0) source and a base, optionally in asuitable solvent, at a temperature ranging from ambient temperature to200 ° C. Suitable sources of palladium (0) include but are not limitedto palladium(II) acetate and tris(dibenzylideneacetone) dipalladium (0).Typical bases for use in the reaction include, for example sodiumtert-butoxide and cesium carbonate.

The reaction can be carried out in neat amine or in a suitable solvent.Toluene is an example of a suitable solvent

As a further example, a compound of formula (I-G) (i.e., a compound offormula (I) wherein q is 1 or more and at least one R⁵ is —O-methyl) maybe converted to a compound of formula (I-H) (i.e., a compound of formula(I) wherein q is 1 or more and at least one R⁵ is —OH) usingconventional demethylation techniques. Additionally, a compound offormula (I-H) may optionally be converted to a compound of formula (I-J)(i.e., a compound of formula (I) wherein q is 1 or more and at least oneR⁵ is —OR¹⁰). For example, the foregoing conversions are representedschematically as follows:

wherein q′ is 1, 2 or 3; Me is methyl, and all other variables are asdefined above.

The demethylation reaction may be carried out by treating a compound offormula (I-G) in a suitable solvent with a Lewis acid at a temperatureof −78° C. to room temperature, to produce a compound of formula (I-H).Typically the solvent is an inert solvent such as dichloromethane,chloroform, acetonitrile, toluene or the like. The Lewis acid may beboron tribromide, trimethylsilyl iodide and the like.

Optionally, a compound of formula (I-H) may be further converted to acompound of formula (I-J) by an alkylation reaction. The alkylationreaction may be carried out by treating a compound of formula (I-H) insuitable solvent with an alkyl halide of formula R¹⁰-Halo where R¹⁰ isas defined above, to form another compound of formula (I-J). Thereaction is preferably carried out in the presence of a base and withoptionally heating to 50-200° C. The reaction may be carried out insolvents such as N,N-dimethylformamide, dimethylsulfoxide and the like.Typically the base is potassium carbonate, cesium carbonate, sodiumhydride or the like. Additionally, as will be apparent to those skilledin the art, the alkylation reaction can be carried out under Mitsunobuconditions.

The foregoing reaction methods can also be used to convert a compound offormula (I) wherein at least one R¹ is —OMe to a compound of formula (I)wherein at least one R¹ is —OH or a compound of formula (I) wherein atleast one R¹ is —OR¹⁰. In another embodiment, the foregoing methods areemployed to make the same conversion when R³ or R⁴ is —OMe, to prepare acompound of formula (I) wherein R³ or R⁴ is —OH or a compound of formula(I) wherein R³ or R⁴ is —OR¹⁰.

In yet another example, a compound of formula (I-K) (i.e., a compound offormula (I) wherein q is 1 or more and at least one R⁵ is halo) or acompound of formula (I-M) (i.e. a compound of formula (I) wherein q is 1or more and at least one R⁵ is nitro) can be converted to a compound offormula (I-L) (i.e., a compound of formula (I) wherein q is 1 or moreand at least one R⁵ is —NH₂). Optionally, a compound of formula (I-L)may then be converted to a compound of formula (I-N) (i.e., a compoundof formula (I) wherein q is 1 or more and at least one R⁵ is —NR⁷R⁸where R⁷ and R⁸ are not both H). For example, the foregoing conversionsare represented schematically as follows:

wherein q′ is 1, 2 or 3, and all other variables are as defined above.

The process of converting a compound of formula (I-K) to a compound offormula (I-L) is carried out by reacting a compound of formula (I-K)with an imine in the presence of a palladium (0) source, a base and asuitable ligand, followed by hydrolysis to give a compound of formula(I-L). See J. Wolfe, et al., Tetrahedron Letters 38:6367-6370 (1997).Typically the imine is benzophenoneimine, the palladium (0) source istris(dibenzylideneacetone)dipalladium(0), the base is sodiumtert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

A compound of formula (I-L) can also be obtained from a compound offormula (I-M) by reduction. The reduction can conveniently be carriedout by using zinc, tin or iron and acid, by using tin(II)chloride, or byusing palladium or platinium catalysts under hydrogen atmosphere in asuitable solvent as will be apparent to those skilled in the art oforganic synthesis.

Reaction of a compound of formula (I-L) with a compound of formulaR⁷-halogen in a suitable solvent in the presence of base, optionallywith heating may be used to prepare a compound of formula (I-N).Typically the base is triethylamine or pyridine and the solvent isN,N-dimethylformamide and the like.

Additional compounds of formula (I-N) can be obtained by reductiveamination of a compound of formula (I-L) with a ketone or aldehyde. See,A. Abdel-Magid, et al., J. Org. Chem. 61:3849-3862 (1996). Typically acompound of formula (I-L) is treated with an aldehyde or a ketone in thepresence of an acid, such as acetic acid, and a reducing agent, such assodium triacetoxyborohydride or the like, in an inert solvent such asdichloroethane or the like.

The foregoing reaction methods can also be used to convert a compound offormula (I) wherein at least one R¹ is halo to a compound of formula (I)wherein at least one R¹ is —NH₂ and a compound of formula (I) wherein atleast one R⁶ is —NR⁷R⁸ (where R⁷ and R⁸ are not both H). In anotherembodiment, the foregoing methods are employed to make the sameconversion when R³ or R⁴ is halo, to prepare a compound of formula (I)wherein R³ or R⁴ is —NH₂ or a compound of formula (I) wherein R³ or R⁴is —NR⁷R⁸ (where R⁷ and R⁸ are not both H).

Other transformations well known to those skilled in the art for usewith anilines may be used to convert a compound of formula (I-L) to acompound of formula (I-N).

Based upon this disclosure and the examples contained herein one skilledin the art can readily convert a compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof into another compound of formula (I), or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof.

The present invention also provides radiolabeled compounds of formula(I) and biotinylated compounds of formula (I). Radiolabeled compounds offormula (I) and biotinylated compounds of formula (I) can be preparedusing conventional techniques. For example, radiolabeled compounds offormula (I) can be prepared by reacting the compound of formula (I) withtritium gas in the presence of an appropriate catalyst to produceradiolabeled compounds of formula (I).

In one embodiment, the compounds of formula (I) are tritiated.

The radiolabeled compounds of formula (I) and biotinylated compounds offormula (I) are useful in assays for the identification of compounds forthe treatment or prophylaxis of viral infections such as herpes viralinfections. Accordingly, the present invention provides an assay methodfor identifying compounds which have activity for the treatment orprophylaxis of viral infections such as herpes viral infections, whichmethod comprises the step of specifically binding the radiolabeledcompound of formula (I) or the biotinylated compounds of formula (I) tothe target protein. More specifically, suitable assay methods willinclude competition binding assays. The radiolabeled compounds offormula (I) and biotinylated compounds of formula (I) can be employed inassays according to the methods conventional in the art.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way, the inventionbeing defined by the claims which follow.

Reagents are commercially available or are prepared according toprocedures in the literature. Example numbers refer to those compoundslisted in the tables above. ¹H and ¹³C NMR spectra were obtained onVarian Unity Plus NMR spectrophotometers at 300 or 400 MHz, and 75 or100 MHz respectively. ¹⁹F NMR were recorded at 282 MHz. Mass spectrawere obtained on Micromass Platform, or ZMD mass spectrometers fromMicromass Ltd. Altrincham, UK, using either Atmospheric ChemicalIonization (APCI) or Electrospray Ionization (ESI). Analytical thinlayer chromatography was used to verify the purity of some intermediateswhich could not be isolated or which were too unstable for fullcharacterization, and to follow the progress of reactions. Unlessotherwise stated, this was done using silica gel (Merck Silica Gel 60F254). Unless otherwise stated, column chromatography for thepurification of some compounds, used Merck Silica gel 60 (230-400 mesh),and the stated solvent system under pressure. All compounds werecharacterized as their free-base form unless otherwise stated. Onoccasion the corresponding hydrochloride salts were formed to generatesolids where noted.

EXAMPLE 13-(2-Fluoropyridin-4-yl)-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine.

a) 2-Fluoropyridin-4ylboronic Acid.

To a stirred solution of n-butyl lithium (3.2 mL, 2.5M, 8.0 mmol) in drydiethyl ether (20 mL) at −78° C. was added a solution of2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and thereaction mixture was stirred at −78° C. for 10 minutes. Tributyl borate(2.4 mL, 2.01 g, 8.7 mmol) was added and the reaction mixture wasallowed to warm to room temperature over 2 hours. Water (5 mL) was addedfollowed by 2N aqueous sodium hydroxide solution (10 mL) to dissolve thesolids. The organic phase was separated. The aqueous phase was acidifiedto pH3 using 6N hydrochloric acid and the resulting white solid wascollected by filtration and dried under vacuum to give the titlecompound, 0.74 g (780%). ¹H NMR (DMSO-d₆) δ 8.65 (br s, 2H), 8.21 (d,1H), 7.59 (t, 1H), 7.37 (d, 1H).

b) 3-Bromo-7-chloro-2-phenylpyrazolo[1,5-α]pyrimidine.

7-Chloro-2-phenylpyrazolo[1,5-α]pyrimidine (0.1 g, 0.44 mmol, preparedas described in J. Med. Chem. 1981, 24, 610) was dissolved indichloromethane (5 mL) and to this solution was added N-bromosuccinimide(108 mg, 0.61 mmol). The resulting reaction mixture was stirred for 30minutes. Additional dichloromethane was added and the mixture wasextracted with sodium hydroxide (1N), water and a saturated aqueoussodium chloride solution. The organic phase was dried over magnesiumsulfate, filtered and concentrated. The resulting solid was purified bysilica gel chromatography (ethyl acetate:hexane 1:2) to give 110 mg(82%) of 3-bromo-7-chloro-2-phenylpyrazolo[1,5-α]pyrimidine as a yellowsolid.

1H NMR (CDCl₃):δ 8.50 (d, 1H), 8.17 (m, 2H), 7.57 (m, 3H), 7.07 (d, 1H);MS m/z 308 (M+1).

c) 3-Bromo-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine.

3-Bromo-7-chloro-2-phenylpyrazolo[1,5-α]pyrimidine (100 mg, 0.32 mmol)was dissolved in ethanol. To this solution was added pyrrolidine (0.5mL) and the reaction mixture heated at reflux for 10 minutes. Theresulting mixture was concentrated in vacuo, then dissolved indichloromethane and the organic phase was washed with water, dried overmagnesium sulfate, filtered and concentrated. The resulting solid wascrystallized from methanol to give 85 mg (77%) of3-bromo-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine as a solid.¹H NMR (CDCl₃):δ 8.17 (m, 3H), 7.50 (m, 3H), 5.80 (d, 1H), 4.09 m (broads, 4H), 2.10 (broad s, 4H); MS m/z 343 (M+1).

d)3-(2-Fluoropyridin-4-yl)-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine.

3-Bromo-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine (150 mg,0.44 mmol) was dissolved in N,N-dimethylformamide (4 mL). To thissolution was added dichlorobis(tripenylphosphine)palladium (II) (60 mg,0.09 mmol), 2-fluoropyridin-4-ylboronic acid (92 mg, 0.66 mmol), sodiumcarbonate (185 mg, 1.76 mmol) and a few drops of water. The resultingsolution was heated at 110° C. for 24 hours. The resulting mixture wasdiluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate, filtered and concentrated. Theresulting black residue was purified by silica gel chromatography (ethylacetate:hexane 1:1) to give 50 mg (32%) of the title compound as a whitesolid. ¹H NMR (CDCl₃):δ 8.17 (d, 1H), 8.08 (d, 1H), 7.60 (m, 2H), 7.41(m, 4H), 7.24 (broad s, 1H), 5.87 (d, 1H), 4.06 (broad s, 4H), 2.07(broad s, 4H); ¹⁹F NMR (CDCl₃):δ −-69.34; MS m/z 360 (M+1).

EXAMPLE 2N-Cyclopentyl-4(2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidin-3-yl)pyridin-2-amineand Example 3N-Cyclopentyl-3-[2-(cyclopentylamino)pyridin-4-yl]-2-phenylpyrazolo[1,5-α]pyrimidin-7-amine

3-(2-Fluoropyridin-4yl)-2-phenyl-7-pyrrolidin-1-yl(pyrazolo[1,5-α]pyrimidine(50 mg, 0.14 mmol) was dissolved in cyclcopentylamine (4 mL) and placedin a pressure tube. Reaction was heated to 150° C. overnight, and thento 165° C. for 2 days. Reaction was cooled to room temperature, thenconcentrated in vacuo to a solid. This solid was purified by silica gelchromatography (ethyl acetate:hexane 1:1) to give 15 mg (25%) ofN-cyclopentyl-4-(2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidin-3-yl)pyridin-2-amineas a foam and 4 mg (7%) ofN-cyclopentyl-3-[2-(cyclopentylamino)pyridin-4-yl]-2-phenylpyrazolo[1,5-α]pyrimidin-7-amine.

ForN-cyclopentyl-4-(2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidin-3-yl)pyridin-2-amine:¹HNMR (CDCl₃):δ 8.14 (d, 1H), 7.99 (d, 1H), 7.64 (m, 2H), 7.38 (m, 3H),6.84 (dd, 1H), 6.56 (s, 1H), 5.80 (d, 1H), 4.68 (broad s, 1H), 4.05(broad s, 4H), 3.77 (m, 1H), 1.3-2.1 (m, 12H); MS m/z 425 (M+1).

ForN-cyclopentyl-3-[2-(cyclopentylamino)pyridin-4-yl]-2-phenylpyrazolo[1,5-α]pyrimidin-7-amine:¹H NMR (CDCl₃):δ 8.30 (d, ₁H), 8.01 (d, 1H), 7.64 (m, 2H), 7.41 (m, 3H),6.86 (dd, 1H), 6.56 (s, 1H), 6.43 (d, 1H), 6.05 (d, 1H), 4.54 (m, 1H),4.08 (m, 1H), 3.77 (m, 1H), 1.3-2.1 (m, 16H); MS m/z 439 (M+1).

EXAMPLE 4N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine

The title compound was prepared in a similar manner as described aboveto give a tan foam. ¹H NMR (DMSO-d₆) δ 8.19 (d, 1H), 7.80 (d, 1H), 7.68(d, 1H), 7.52 (d, 2H), 6.99 (d, 2H), 6.68 (s, 1H), 6.47 (d, 1H), 6.39(br s, 1H), 6.31 (d, 1H), 4.15-4.05 (m, 1H), 3.95-3.88 (m, 1H), 3.78 (s,3H), 2.1-1.3 (m, 16H); MS m/z 469 (M+1). Anal. Calcd. for C₂₈H₃₂N₆O. 0.3H₂O: C, 70.95; H, 6.93; N, 17.73. Found: C, 70.96; H, 6.91; N, 17.70.

EXAMPLE 5N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyrimidin-7-amine

The title compound was prepared in a similar manner as described aboveto give a tan foam. ¹H NMR (CDCl₃) δ 8.30 (d, 1H), 8.02 (d, 1H), 7.63(dd, 2H), 7.12 (t, 2H), 6.80 (d, 1 H), 6.55 (s, 1H), 6.39 (d, 1H), 6.05(d, 1H), 4.55 (br s, 1H), 4.1-4.0 (m, 1H), 3.85-3.75 (m, 1 H), 2.2-1.4(m, 16H); MS m/z 457 (M+1).

EXAMPLE 6N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine

a)N-Cyclopentyl-3-iodo-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine.

To a solution of 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidine(0.25 g, 0.96 mmol) in dichloromethane (8 mL) was addedN-iodosuccinimide. The reaction was stirred at room temperature for 2hours before being diluted with dichloromethane (50 mL). The solutionwas washed with aqueous 2M sodium hydroxide (50 mL) and concentrated.The residue was dissolved in cyclopentylamine (5 mL) and stirredovernight at room temperature. The mixture was concentrated and theresidue purified by silica chromatography, eluting with 5% acetone indichloromethane to yield 190 mg (45%) ofN-cyclopentyl-3-iodo-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine.MS m/z 435 (M+1).

b) 2-(Methylsulfanyl)-4-(tributylstannyl)pyrimidine.

To a solution of 4-iodo-2-(methylsulfanyl)pyrimidine (1.0 g. 4.0 mmol)in tetrahydrofuran (6 ml) was added 1,1,1,2,2,2-hexabutyldistannane (4.1mL, 8.2 mmol), bis(triphenylphoshine)palladium(III)acetate (0.090 g,0.12 mmol), and 1M tetrabutylammonium fluoride in tetrahydrofuran (12mL, 12 mmol). The mixture was stirred for 3 hours at room temperatureand concentrated. The residue was taken up in ethyl acetate, washed withwater before being dried over magnesium sulfate. The solution wasfiltered, concentrated and the residue purified by silicachromatography, eluting with 100% ethyl acetate in hexanes to yield 0.34g (37%) of 2-(methylsulfanyl)-4-(tributylstannyl)pyrimidine. MS m/z 416(M+1).

c)N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine.

N-Cyclopentyl-3-iodo-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine(63 mg, 0.15 mmol), dichlorobis(triphenylphosphine)palladium(II) (25 mg,0.015 mmol), and 2-(methylsulfanyl)-4-(tributylstannyl)pyrimidine (78mg, 0.19 mmol) were added to toluene (3 mL) and heated to 110° C. for 16hours. Additional dichlorobis(triphenylphosphine)palladium(II) (6 mg)was added and the reaction heated to 110° C. for 24 hours. The reactionwas allowed to cool to room temperature, diluted with ethyl acetate,poured into 10% aqueous potassium fluoride containing 1% methanol, andstirred for 20 minutes before being extracted with ethyl acetate. Theorganic phase was concentrated and the residue purified by silicachromatography, eluting with a gradient of 5% to 10% acetone indichloromethane to yield 25 mg of an approximate 1:1 mixture ofN-cyclopentyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine andN-cyclopentyl-2-(4-methoxyphenyl)-3-[2-(methylsulfanyl)pyrimidin-4yl]pyrazolo[1,5-α]pyrimidin-7-amine.To a 0° C. solution of this mixture in dichloromethane (1 mL) was added3-chloroperoxybenzoic acid (0.099 mg, 0.058 mmol). The mixture wasallowed to warm to room temperature and stirred for 2 hours. The mixturewas diluted with dichloromethane, washed with saturated aqueous sodiumbicarbonate, and concentrated. The residue was dissolved incyclopentylamine and stirred at room temperature for 2.5 hours. Themixture was concentrated and the residue purified by silicachromatography, eluting with a gradient of 5% to 15% acetone indichloromethane to yield 14 mg (11%) ofN-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine.¹H NMR (CDCl₃):δ 8.37 (d, 1H), 8.26 (d, 1H), 7.67 (d, 2H), 6.99 (d, 2H),6.50 (d, 1H), 6.11 (d, 1H), 5.01 (m, 1H), 4.09 (m, 1H), 3.90 (s, 3H),2.20 (m, 2H), 1.75 (m, 14H); MS m/z 470 (M+1).

EXAMPLE 7 Biological Activity

In the following example, “MEM” means Minimal Essential Media; “FBS”means Fetal Bovine Serum; “NP40” and “Igepal” are detergents; “MOI”means Multiplicity of Infection; “NaOH” means sodium hydroxide; “MgCl₂”means magnesium chloride; “dATP” means deoxyadenosine 5′ triphosphate;“dUTP” means deoxyuridine 5′ triphosphate; “dCTP” means dexoxycytidine5′ triphosphate; “dGTP” means deoxyguanosine 5′ triphosphate; “GuSCN”means Guanidinium thiocyanate; “EDTA” means ethylenediamine tetraaceticacid; “TE” means Tris-EDTA; “SCC” means sodium chloride/sodium citrate;“APE” means a solution of ammonia acetate, ammonia phosphate, EDTA;“PBS” means phosphate buffered saline; and “HRP” means horseradishperoxidase.

a) Tissue Culture and HSV Infection.

Vero 76 cells were maintained in MEM with Earle's salts, L-glutamine, 8%FBS (Hyclone, A-1111-L) and 100 units/mL Penicillin-100 μg/mLStreptomycin. For assay conditions, FBS was reduced to 2%. Cells areseeded into 96-well tissue culture plates at a density of 5×10⁴cells/well after being incubated for 45 min at 37° C. in the presence ofHSV-1 or HSV-2 (MOI=0.001). Test compounds are added to the wells andthe plates are incubated at 37° C. for 40-48 hours. Cell lysates areprepared as follows: media was removed and replaced with 150 μL/well 0.2N NaOH with 1% igepal CA 630 or NP-40. Plates were incubated up to 14days at room temperature in a humidified chamber to prevent evaporation.

(b) Preparation of detection DNA.

For the detection probe, a gel-purified, digoxigenin-labeled, 710-bp PCRfragment of the HSV UL-15 sequence was utilized. PCR conditions included0.5 μM primers, 180 μM dTTP, 20 μM dUTP-digoxigenin (Boehringer Mannheim1558706), 200 μM each of dATP, dCTP, and dGTP, 1× PCR Buffer II (PerkinElmer), 2.5 mM MgCl₂, 0.025 units/μL of AmpliTaq Gold polymerase (PerkinElmer), and 5 ng of gel-purified HSV DNA per 100 μL Extension conditionswere 10 min at 95° C., followed by 30 cycles of 95° C. for 1 min, 55° C.for 30 sec, and 72° C. for 2 min. The amplification was completed with a10-min incubation at 72° C. Primers were selected to amplify a 728 bpprobe spanning a section of the HSV1 UL15 open reading frame(nucleotides 249-977). Single-stranded transcripts were purified withPromega M13 Wizard kits. The final product was mixed 1:1 with a mixtureof 6 M GuSCN, 100 mM EDTA and 200 μg/mL herring sperm DNA and stored at4° C.

(c) Preparation of Capture Plates.

The capture DNA plasmid (HSV UL13 region in pUC) was linearized bycutting with Xba I, denatured for 15 min at 95° C. and dilutedimmediately into Reacti-Bind DNA Coating Solution (Pierce, 17250,diluted 1:1 with TE buffer, pH 8) at 1 ng/μL. 75 μL/well were added toCorning (#3922 or 9690) white 96-well plates and incubated at roomtemperature for at least 4 hrs before washing twice with 300 μL/well0.2×SSC/0.05% Tween-20 (SSC/T buffer). The plates were then incubatedovernight at room temperature with 150 μL/well 0.2 N NaOH, 1% IGEPAL and10 μg/mL herring sperm DNA.

(d) Hybridization.

Twenty-seven (27) μL of cell lysate was combined with 45 μL ofhybridization solution (final concentration: 3M GuSCN, 50 mM EDTA, 100μg/ml salmon sperm DNA, 5× Denhardt's solution, 0.25× APE, and 5 ng ofthe digoxigenin-labeled detection probe). APE is 1.5 M NH₄-acetate, 0.15M NH₄H₂ phosphate, and 5 mM EDTA adjusted to pH 6.0. Mineral oil (50 μL)was added to prevent evaporation. The hybridization plates wereincubated at 95° C. for 10 minutes to denature the DNA, then incubatedat 42° C. overnight. The wells were washed 6× with 300 μL/well SSC/Tbuffer then incubated with 75 μL/well anti-digoxigenin-HRP-conjugatedantibody (Boehringer Mannheim 1207733, 1:5000 in TE) for 30 min at roomtemperature. The wells were washed 6× with 300 μL/well with PBS/0.05%Tween-20 before 75 μL/well SuperSignal LBA substrate (Pierce) was added.The plates were incubated at room temperature for 30 minutes andchemiluminescence was measured in a Wallac Victor reader.

e) Results.

The following results were obtained for HSV-1.

Example No. IC₅₀ (μM) 1 28 2 0.8 3 0.3 4 0.6 5 1.2 6 2.4

The results demonstrate that the compounds of the present invention areuseful for the treatment and prophylaxis of herpes viral infections.

1. A compound of formula (I):

wherein: p is 1, 2 or 3; each R¹ is the same or different and isindependently selected from the group consisting of halo, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay,—C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,—C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹, —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹,—R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,—R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and azido;each R⁷ and R⁸ are the same or different and are independently selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂R¹², —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂R¹² and —R¹⁰SO₂NHCOR⁹; each R⁹ and R¹¹ are the same or differentand are independently selected from the group consisting of H, alkyl,cycloalkyl, —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹²)_(w) where w is 1-10, and—R¹⁰NR¹²R¹²; “R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkylene, cycloalkylene, alkenylene,cycloalkenylene, and alkynylene;” each R¹² is the same or different andis independently selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; Ay is aryl; Het is a 5-or 6-membered heterocyclic or heteroaryl group; n is 0, 1 or 2; Y is Nor CH; R² is selected from the group consisting of Ay, Het, —OAy, —OHet,—OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ and R⁴ are thesame or different and are each independently selected from the groupconsisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, —C(O)R⁷,—C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay,—NHHet, —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; Ring A is selected from the group consisting of aryl, 5-10membered heterocyclic group and a 5-10 membered heteroaryl group; q is0, 1, 2, 3, 4 or 5; and each R⁵ is the same or different and isindependently selected from the group consisting of halo, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay,—C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,—C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹,cyano, nitro and azido; or a pharmaceutically acceptable salt, thereof.2. The compound according to claim 1 wherein each R¹ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷,—OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay,—NHR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, cyano, nitro and azido.
 3. The compound according to claim1 wherein each R¹ is the same or different and is independently selectedfrom the group consisting of halo, Ay, Het and —NR⁷R⁸.
 4. The compoundaccording to claim 1 wherein p is
 1. 5. The compound according to claim1 wherein Y is OH.
 6. The compound according to claim 1 wherein Y is N.7. The compound according to claim 1 wherein R² is selected from thegroup consisting of Het, —NR⁷R⁸, —NR⁷Ay, —NHHet and —S(O)_(n)R⁹.
 8. Thecompound according to claim 1 wherein R² is selected from the groupconsisting of Het and —NR⁷R⁸.
 9. The compound according to claim 1wherein R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, Ay, —OR⁷, —CO₂R⁷,—NR⁷R⁸, —R¹⁰OR⁷ and —R¹⁰NR⁷R⁸.
 10. The compound according to claim 1wherein R³ and R⁴ are both H.
 11. The compound according to claim 1wherein Ring A is selected from the group consisting of aryl, a 5-6membered heterocyclic or heteroaryl group and a 9-membered heterocyclicor heteroaryl group.
 12. The compound according to claim 1 wherein RingA is selected from the group consisting of phenyl, naphthyl, furan,pyridine, pyrimidine, thiazole, pyrazine, pyrrole, imidazole, oxazole,berizimidazole, quinoline, isoquinoline and quinoxoline.
 13. Thecompound according to claim 1 wherein Ring A is selected from the groupconsisting of phenyl, furan, pyridine and pyrimidine.
 14. The compoundaccording to claim 1 wherein Ring A is phenyl.
 15. The compoundaccording to claim 1 wherein q is 0,1 or
 2. 16. The compound accordingto claim 1 wherein each R⁵ is the same or different and is independentlyselected from the group consisting of halo, alkyl, alkenyl, Ay, Het,—CO₂R⁹, —C(O)NR⁷R⁸, —OR⁷, —OAy, —NR⁷R⁸, —NR⁷Ay, —S(O)₂NR⁷R⁸, cyano,nitro and azido.
 17. The compound according to claim 1, wherein each R⁵is the same or different and is independently selected from the groupconsisting of halo, alkyl, —OR⁷, —NR⁷R⁸ and cyano.
 18. A compoundselected from the group consisting of:3-(2-Fluoropyridin-4-yl)-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine;N-Cyclopentyl-4-(2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidin-3-yl)pyridin-2-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)pyridin-4-yl]-2-phenylpyrazolo[1,5-α]pyrimidin-7-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyrimidin-7-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl-]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyrimidin-7-amine;andN-Cycloperltyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[15-α]pyrimidin-7-amine,or a pharmaceutically acceptable salt, thereof.
 19. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier or diluent.
 20. A method for thetreatment of a herpes viral infection selected from herpes simplex virus1 and herpes simplex virus 2, in an animal, said method comprisingadministering to the animal a therapeutically effective amount of acompound according to claim
 1. 21. A process for preparing a compoundaccording to claim 1 comprising reacting the compound of formual(VII-A):

wherein X is chloro, bromo or iodo; with a compound of formula (VIII):

wherein M is selected from the group consisting of —B(OH)₂, —B(ORa)₂,—B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, Mg-halide where Ra is alkyl orcycloalkyl and halide is halo; to prepare a compound of formula (I).